Organ transplant rejections, autoimmune diseases, allergies, etc. are caused when the immune system responsible for defending the body activates the defense system against antigens other than the body itself to destroy the transplanted organ or tissue and thus have deleterious effects on the human body. In general, the organ transplant is the most effective treatment for patients with end-stage organ failure. However, if major histocompatibility (MHC) genes of donor and recipient do not match, the body's immune system recognizes the transplanted organ as harmful germs and attacks the transplanted organ by activating T lymphocytes, B lymphocytes, macrophages, or natural killer (NK) cells, etc. The regulation of the unwanted immune response is called immunomodulation, and drugs used for immunomodulation are called immunomodulators. Cyclosporin A, tacrolimus (hereinafter referred to as FK506), etc. have been developed so far as the immunomodulators.
Cyclosporin A was isolated from Trichoderma polysporum in 1976 and has been reported to have relatively fewer side effects and to reduce bacterial infection compared to other immunomodulators. Moreover, FK506 isolated from Streptomyces tsukubaensis has been reported to have efficiency 10 to 100 times higher than that of cyclosporin A. However, the cyclosporin A and FK506 have side effects such as severe renal toxicity, liver toxicity, etc.
Meanwhile, colchicine is an alkaloid drug used for treatment of gout and has been reported to inhibit the function of tubulin, a protein known to act as both muscle and skeleton, by binding to the tubulin. Colchicine has been reported to have anticancer and antiproliferative activities and has been widely used for treatment of psoriasis or rheumatoid arthritis, treatment of amyloidosis and inflammation, etc. Moreover, Korean Patent No. 324302 and Korean Patent Publication No. 2002-30296 disclose the use of colchicine as an immunomodulator. However, the colchicine has a low effect compared to dose and is highly toxic at high dose, and thus the development of a new improved immunomodulator is urgently needed.
Accordingly, the present inventors have prepared new colchicine derivatives through various synthetic routes and confirmed that the colchicine derivatives exhibit superior immunomodulatory effects and low toxicity compared to conventional immunomodulators and colchicines, thus completing the present invention.